burden of substance use disorder (SUD) is highest in late adolescence and young adulthood and then decreases rapidly in young adulthood. A similar developmental pattern is seen for some aspects of self-regulation (risk-taking, reward-seeking), whereas other aspects improve steadily across development (cognitive control, affective-cognitive coordination, self-regulatory efficiency) . This developmental pattern prioritizes adolescence as a key period for understanding how converging biological changes alter risk for SUDs. Adolescence begins with a biologically-driven developmental transition - puberty - which has complex secondary effects on social, emotional, and sexual development. Adolescence also brings major changes in neurodevelopment, including brain physiology and, which may heighten vulnerability to the effects of substance exposures on brain development. It is in this context of neural development and novel environmental challenges that small genetic differences can affect risk for problematic substance use. Implications. To understand the reciprocal interplay between self-regulation and adolescent substance use, studies must incorporate biological methods. To illustrate our approach, we present 3 examples of ways in which we propose to advance knowledge of self-regulation and SUD: genetics, imaging, and biomarkers.